Recent advances in genomic sciences, high throughput technologies, and infusion of domain-experts from various quantitative subjects have created new opportunities for identifying many of the genes commonly implicated in diseases, and elucidating many of the cellular pathways upon which they act. Advances in the genomic sciences include component technologies generally explored within various mapping approaches such as, e.g., optical mapping and array-mapping techniques. Such techniques are described, e.g., in Z. Lai. et al., “A Shotgun Sequence-Ready Optical Map of the Whole Plasmodium falciparum Genome,” Nature Genetics, 23(3): 309-313, 1999; A Lim et al., “Shotgun optical maps of the whole Escherichia coli O157:H7 genome,” Genome Research, 11(9): 1584-93, September 2001; W. Casey, B. Mishra and M. Wigler, “Placing Probes along the Genome using Pair-wise Distance Data,” Algorithms in Bioinformatics, First International Workshop, WABI 2001 Proceedings, LNCS 2149:52-68, Springer-Verlag, 2001; B. Mishra, “Comparing Genomes,” Special issue on “Biocomputation:” Computing in Science and Engineering., pp 42-49, January/February 2002; J. West, J. Healy, M. Wigler, W. Casey, and B. Mishra, “Validation of S. pombe Sequence Assembly by Micro-array Hybridization,” Journal of Computational Biology, 13(1): 1-20, January 2006.
For example, after a decade-long effort directed at optical mapping, single molecule optical mapping technology was developed for clones in 1998 (see, e.g., J. Jing et al., “Automated High Resolution Optical Mapping Using Arrayed, Fluid Fixated, DNA Molecules,” Proc. Natl. Acad. Sci. USA, 95:8046-8051, 1998) and for whole microbial genomes in 1999 (see, e.g., J. Lin et al. “Whole-Genome Shotgun Optical Mapping of Deinococcus radiodurans,” Science, 285:1558-1562, September 1999). In particular, a genome wide restriction map of a single nucleic acid molecule, e.g., double stranded DNA, may be generated using optical mapping techniques, e.g., fluorescent microscopy (see, e.g., J. Jing et al., “Automated High Resolution Optical Mapping Using Arrayed, Fluid Fixated, DNA Molecules,” Proc. Natl. Acad. Sci. USA, 95:8046-8051, 1998).
An ordinarily skilled artisan would know how to generate a genome wide restriction map. Briefly, uncloned DNA (e.g., DNA directly extracted from cells after lysis) may be randomly sheared into approximately 0.1-2 Mb pieces and attached to a charged glass substrate, where the DNA may be cleaved with a restriction enzyme, then stained with a dye (e.g., a fluorescent dye). The restriction enzyme cleavage sites appear as breakages in the DNA under e.g., a fluorescent microscope. Using predefined techniques, the optical mapping of breakages produces a genome wide restriction map.
Although optical mapping methods have been used to generate genome wide restriction maps of whole prokaryotic and eukaryotic genomes, such methods have not been used for generating genome wide haplotype sequences.
Accordingly, at least one of the objects of the invention is to address such deficiencies and issues.